Neuroanesthesiology Review—2007

Autor(es): Pasternak, Jeffrey J. MD; Lanier, William L. MD

Número: Volume 20(2), April 2008, pp 78-104

Tipo de publicación: [Review Article]

Editor: © 2008 Lippincott Williams & Wilkins, Inc.

Instituciones:

Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MNReprints: Jeffrey J. Pasternak, MD, Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First Avenue SW, Rochester, MN 55905 (e-mail: Pasternak.jeffrey@mayo.edu).Received for publication December 27, 2007; accepted January 3, 2008

Palabras clave: subarachnoid hemorrhage, traumatic brain injury, neuroprotection, spine surgery, carotid endarterectomy

Abstract

The 2007 literature pertaining to perioperative care of neurosurgical patients contains a wealth of articles. In this review, we provide a synopsis of common themes and unique contributions that are relevant to the care of patients with neurologic disorders who require either neurosurgical intervention or care in a neurosurgical-based intensive care unit.

Our goal is to provide a synopsis of selected literature published in 2007 that is particularly relevant to readers who deliver perioperative care to patients requiring neurosurgical interventions or intensive care for neurologic disorders. This is by no means a comprehensive review, but is instead a review of common themes and significant or unique articles. We will address 6 broad topics: general neuroanesthesia, subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), carotid endarterectomy, neuroprotection, and spine surgery.

GENERAL NEUROANESTHESIAAnesthetic Techniques

Anesthetic goals for patients receiving general anesthesia for neurosurgical procedures include maintenance of stable hemodynamics and optimization of operative conditions while allowing for sufficiently rapid return of consciousness to facilitate neurologic assessment at the end of the procedure. Magni et al 1 compared the influence of propofol-remifenanil and sevoflurane-fentanyl anesthetic techniques on complication rates in 162 patients undergoing elective craniotomy. With both anesthetic regimens, drug doses were decreased (in a nonreported manner) at bone flap replacement and discontinued after head dressings were applied. The authors report a very high complication rate, 57% overall, however, many of the so-called complications were laboratory based and

related to exceptionally rigid thresholds (ie, all patients had routine blood gas assessment postoperatively at various time intervals and PaO2<90 mm Hg or PaCO2>45 mm Hg were noted as complications even when patients seemed to be clinically stable without clinical signs of hypoxia or hypercarbia). Specific complication rates in the recovery ward were shivering (18%), pain (24%), nausea or vomiting (13%), hypertension defined as mean arterial pressure >130% baseline blood pressure (13%), neurologic complications which the authors did not define (3%), PaO2<90 mm Hg (11%), PaCO2>45 mm Hg (11%), and patients requiring reintubation of the trachea (1%). The authors did not find differences between groups with respect to overall complication rate or the rates of specific complications, however, they did find that respiratory complications were most likely to occur in the initial 30 minutes after anesthesia, and American Society of Anesthesiologists Physical Classification Score was positively correlated with complication rate. As patients having supratentorial and infratentorial craniotomies were included in this study, it would have been interesting to see if a difference in specific complications segregated according to surgical location, however, the authors felt that the study design lacked sufficient statistical power for such an analysis.

Bilotta et al 2 compared the effect of remifentanil versus sufentanil infusions on early cognitive function in 60 patients having craniotomy with background propofol anesthesia. Propofol was adjusted to maintain a bispectral index (BIS) of 40 to 50, and narcotic infusion rates were adjusted to maintain mean arterial pressure within 10% of baseline values. Sufentanil was discontinued at replacement of the bone flap, and remifentanil was discontinued after application of the head dressings. Although the groups had similar total propofol usage [2321±681 mg (mean±SD) and 2355±691 mg for remifentanil and sufentanil, respectively, P>0.05], intraoperative hemodynamics, extubation and recovery times, and pain scores in the recovery ward [as assessed by the visual analog pain scale (VAPS)], patients who received sufentanil seemed to have slower return of cognitive function. Specifically, patients who received sufentanil performed worse on the Short Orientation Memory Concentration Test up to 3 hours after anesthesia. These results may not only reflect differences in the pharmacokinetics of these drugs but also may reflect differences in anesthetic technique (ie, had the authors terminated the sufentanil earlier in the surgical procedure, a different finding may have been identified). The authors did not comment on the impact of the delayed return of cognitive function with sufentanil on assessment of gross neurologic function.

Cafiero et al 3 compared recovery characteristics in patients undergoing transsphenoidal pituitary surgery with an intravenous remifentanil infusion and either sevoflurane or propofol titrated to maintain a mean arterial blood pressure of 60 to 75 mm Hg. All drugs were discontinued when the surgeon removed the endoscope from the nose and no comment was made about reducing drug dosages at earlier timepoints near the end of surgery. Despite a lack of difference between groups with respect to intraoperative hemodynamics, surgical site bleeding, or remifentanil requirements, the authors found that time to response to verbal command and time to orientation as well as Aldrete scores 4 (ie, a metric used to assess suitability of patients for discharge from the postanesthesia recovery unit) were all significantly less in the group that received sevoflurane. The findings of this study and the two described above illustrate an important issue regarding investigations of this type. Many studies have attempted to determine the most favorable maintenance drugs to facilitate an optimal neuroanesthetic. It seems that, with the exception of various drugs that should clearly be avoided (ie, high-dose ketamine), the optimal technique may depend more on how drugs are used rather than the specific drug choices.

Consistent with this concept, Dagtekin et al 5 described the use of pharmacokinetic simulation software (TIVA-trainer, Version 5.1, Leiden University Medical Center, Leiden, Netherlands) to guide both remifentanil and propofol infusions during 21 stereotactic neurosurgical procedures. Changes in drug infusion rates were guided by either electrophysiologic parameters [ie, BIS (N=11; BIS A2000, version 3.4, Aspect Medical System, Newton, MA) or auditory-evoked potentials (N=10; Alaris AEP Monitor, Alaris Medical Systems, San Diego, CA)], various changes in vital signs, or procedural events (ie, completion of the procedure, removal of the stereotactic headframe). The authors reported good control of hemodynamics, rapid emergence from general anesthesia [tracheal extubation in 6 min (range: 5 to 10 min)], and no known complications or adverse events. Of note, the authors reported that some patients undergoing stereotactic intracranial procedures require magnetic resonance imaging. It would seem impossible to adhere to this protocol during magnetic resonance imaging given that it requires electrophysiologic monitoring, which is contraindicated during this imaging technique owing to ferromagnetic material contained within the monitoring devices. Lobo and Beiras 6 used TIVA-trainer software (version 7.5 available at www.eurosiva.org ) to characterize effect-site concentrations (ie, expected brain

concentrations) of both remifenanil and propofol at various points in asleep-awake-asleep craniotomies (eg, each episode of loss of consciousness and each episode of return of consciousness). Changes in drug infusion rates were guided by BIS, hemodynamics, and surgical events; however, specific guidelines describing how each individual infusion was titrated were not stated in the manuscript. This leaves one to wonder if the same type of clinical effect can be obtained with a variety of effect-site concentrations of propofol and remifentanil. Although the effect-site concentration technique is interesting from an academic standpoint, overreliance on the technique could jeopardize utilization of the nuanced corrections and adjustments that only a professional anesthesia provider can make.

Anesthesia for patients undergoing awake craniotomy poses unique challenges for the anesthesiologist, such as administering effective sedation without excessive respiratory depression, or, as in the asleep-awake-asleep technique, instrumenting an airway with limited access. Frost and Booij 7 published a brief review of current literature dealing with anesthetic management in patients requiring awake craniotomy. This review focuses specifically on drugs with unique pharmacologic properties (ie, remifentanil, propofol, and dexmedetomidine) that make them appealing for use in this patient population.

An abstract published in 2003 raised concern about the use of dexmedetomidine concomitantly with electrocorticography during general anesthesia for seizure focus identification because of potential suppression of epileptiform activity.8 In this abstract, dexmedetomidine was used in conjunction with sevoflurane. We identified 2 investigations published in 2007, which suggested that dexmedetomidine does not suppress epileptiform activity, thus allowing for successful electrocorticographic identification of seizure foci. Souter et al 9 successfully used dexmedetomidine during both an asleep-awake-asleep technique in combination with propofol and as a sole agent for awake craniotomy performed via sedation only. In fact, they report that in 2 cases performed via sedation only, the dexmedetomidine infusion was continued throughout awake mapping without difficulty. Talke et al 10 evaluated the effect of dexmedetomidine on electroencephalographically measured epileptiform activity in 5 patients undergoing in-hospital video electroencephalographic monitoring. All patients received an intravenous bolus of 0.5-mcg/kg dexmedetomidine over 10 minutes followed by a 50 minute infusion at a rate of 0.5 mcg/kg/h. Epileptiform discharges per 15 minutes epoch were counted. Before administering dexmedetomidine, epileptiform activity was 1.5±1.5 discharges/epoch. During the infusion, epileptiform activity increased. For the hour after infusion termination, the frequency of discharges was similar to, or slightly greater than, baseline. Furthermore, not only did the authors report that subclinical seizure activity still occurred during the study period, but that in many cases, the electroencephalographic tracing during the seizure was of greater amplitude and of a more complex pattern than activity documented before administration of dexmedetomidine. In light of these recent data, dexmedetomidine can probably be used safely in cases where electrocorticography is employed, provided that other drugs that may suppress epileptiform activity are avoided.

Patients requiring permanent occlusion of a major cerebral artery (eg, supplying an aneurysm or tumor), who have inadequate collateral circulation, may require a bypass procedure where a graft is anastomosed from an extracranial artery to the occluded intracranial artery. These surgical procedures often require temporary occlusion of a known compromised circulation while performing the anastomosis. Muench et al 11 report on their experience providing anesthesia to patients undergoing a bypass procedure with an exciter laser-assisted distal anastomosis, thus avoiding the need for temporary occlusion. In this procedure, a saphenous vein graft is sutured to the recipient intracranial artery and an exciter laser is advanced via the vein graft to the arterial wall. The laser is then activated and, with concurrent vacuum, an arteriotomy is opened. The laser is then removed and the vein graft is temporarily clamped while the proximal anastomosis to an extracranial vessel is performed. After this, the temporary clamp is removed and flow to the compromised vessel occurs via the bypass. The authors reported on 29 cases: 27 for giant aneurysms (22 in the anterior and 4 in the posterior circulation), and 2 for skull base tumors with carotid artery involvement. The authors reported stable hemodynamics and no adverse events using a propofol/narcotic-based anesthetic. Typical procedures required 10±2 hours of anesthesia, blood loss was 890±540 mL, and the postoperative blood pressure goal was a systolic blood pressure of 140 to 160 mm Hg.

Nausea and Vomiting After Craniotomy

Nausea and vomiting are very common after craniotomy and can be quite problematic. The incidence of nausea and vomiting is variable but can be as great as 70% for nausea and 55% for vomiting.12 Furthermore, nausea is a source of patient discomfort, and vomiting can lead to electrolyte disturbances, brief increases in intracranial pressure (ICP), aspiration, and new-onset intracranial bleeding.12,13 Because of their favorable side-effect profile, 5-hydroxytryptamine type-3 receptor antagonists are commonly used either to prevent or treat postoperative nausea and vomiting (PONV) after general anesthesia. Neufeld and Newburn-Cook 14 recently published a meta-analysis studying the effectiveness of 5-hydroxytryptamine type-3 receptor antagonists at preventing PONV after craniotomy. The authors included only prospective, randomized, placebo-controlled trials involving adults in their analysis, and both supratentorial and infratentorial craniotomy cases were included. Seven investigations were included and consisted of 222 patients who received at least a 5-hydroxytryptamine type-3 receptor antagonist and 226 patients who received placebo. Prophylactic treatment with 5-hydroxytryptamine type-3 receptor antagonists did not decrease the risk of nausea at 24 hours [relative risk (RR)=0.76, 95% confidence interval (CI)=0.54-1.06; P=0.11] or 48 hours (RR=0.81, 95% CI=0.62-1.06; P=0.13) but did significantly reduce the incidence of vomiting at both 24 hours (RR=0.50, 95% CI=0.38-0.66; P<0.00001) and 48 hours (RR=0.52, 95% CI=0.36-0.75; P=0.0005) after craniotomy. Although this meta-analysis had limitations, it seems to have been well conducted. Pending sufficiently detailed information from the studies analyzed, it would be useful to know the effect of this class of drugs on subpopulations within the treatment group; such as supratentorial versus infratentorial craniotomy, temporal lobe versus nontemporal lobe supratentorial craniotomy, and type of anesthetic administered for maintenance of general anesthesia.

The corticosteroid dexamethasone is reported to be effective at reducing PONV.15 Dexamethasone is also very effective at reducing vasogenic edema that may surround intracranial tumors and is often administered to patients with brain tumors to reduce neurologic symptoms while they await surgical resection. Dexamethasone, when administered in the perioperative period, has been reported to have synergistic effects at reducing PONV when given in conjunction with 5-hydroxytryptamine type-3 receptor antagonists.16 In a prospective, randomized trial, Wig et al 17 evaluated whether prophylactic ondansetron is effective at reducing the incidence of nausea or vomiting in patients taking preoperative dexamethasone for its effect on vasogenic edema. Seventy adults who were taking dexamethasone for at least 24 hours before craniotomy were randomized to receive either placebo or 4-mg ondansetron intravenously upon dural closure. Similar to the meta-analysis described in the prior paragraph, ondansetron reduced the overall incidence of vomiting (23% in treatment and 46% in control groups; P=0.044) but not that of nausea (31% in treatment and 54% in control groups; P=0.053). These results are somewhat predictable given that one would not have expected dexamethasone to interfere with the action of other antiemetic agents. Perhaps, a future study design should compare the effectiveness of dexamethasone, used for the treatment of cerebral edema, on the incidence of nausea and vomiting after craniotomy, because whether preoperative doses of dexamethasone are effective at reducing PONV is currently unknown.

In an earlier investigation, use of single-dose ondansetron was not effective at reducing the incidence of PONV in children having craniotomy.13 This result may have been due to the shorter terminal half-life of ondansetron in this population.18 Subramaniam et al 19 investigated whether repeated doses of ondansetron were effective at reducing the incidence of PONV in children undergoing craniotomy. Ninety children having craniotomy were randomized to receive either placebo or ondansetron administered either as a single dose at dural closure or as 2 doses administered at dural closure and again 6 hours later. Ondansetron was administered as a 150-mcg/kg intravenous bolus and data from 75 children were included in the final analysis. The authors found no difference in the incidence of nausea or vomiting among groups. Specifically, the 24-hour incidence of nausea alone was 4% for placebo, 15% for single-dose, and 8% for double-dose ondansetron (P=0.489). The 24-hour incidence of vomiting was 33% for placebo, 12% for single-dose, and 24% for double-dose ondansetron (P=0.246). Furthermore, the authors reported no difference in the combined incidence of nausea and vomiting in those children who were receiving preoperative dexamethasone for the treatment of peritumoral vasogenic edema (24%) versus those who were not receiving preoperative dexamethasone treatment (39%) (P=0.273). Also, the combined incidence of PONV was not different between those having supratentorial (30%) and infratentorial craniotomy (38%) (P=0.480). The authors state that their investigation was probably underpowered to detect statistically significant differences among subgroups. The conflicting effectiveness of 5-hydroxytryptamine type-3 receptor antagonists at reducing the incidence of vomiting between adults and children is almost certainly multifactorial and probably

consists of pharmacokinetic and pharmacodynamic differences, differences in the incidence of supratentorial versus infratentorial surgery, and tumor type and location, as well as different stratification of risk factors for nausea and vomiting (ie, the incidence of motion sickness in children vs. adults).

Fluid Management for Craniotomy

Brain relaxation during craniotomy is commonly induced using hyperventilation, hypertonic fluids, diuretics, and cerebrospinal fluid drainage. Hypertonic fluids and diuretics produce brain relaxation by decreasing brain water content. There are conflicting data regarding the efficacy of mannitol versus hypertonic saline for the treatment of increased ICP, with hypertonic saline reported to be either as effective or more effective than mannitol.20–22 Two trials reported similar effects for mannitol and hypertonic saline on ICP management, however, the solutions administered had different osmotic loads, which could significantly confound the results.23,24 Rozet et al 25 randomized 40 adult patients undergoing craniotomy requiring lumbar cerebrospinal fluid drainage via a standardized anesthetic technique to receive 5 mL/kg of either 20% mannitol (osmolarity=1098 mOsm/L) or 3% sodium chloride (osmolarity=1024 mOsm/L) administered over 15 minutes after skin incision. Brain relaxation was assessed by the surgeon and graded on a 4-point scale (1=perfect relaxation, 2=satisfactory relaxation, 3=firm brain, 4=bulging brain) and, if adequate relaxation was not achieved, a second 5-mL/kg bolus of study fluid was administered in addition to cerebrospinal fluid aspiration and hyperventilation. There was no difference in demographics, pathology, or severity of SAH in patients with SAH. There was no difference in the degree of brain relaxation overall between groups or in subgroups of those with and without SAH. Those who received mannitol had greater urine output during the first 3 hours after administration (2248±1443 mL) compared with those who received hypertonic saline (908±829 mL; P=0.001), but this difference was not significant at 6 hours postadministration. Both fluids produced similar changes in serum osmolarity. After administration of mannitol, there was an immediate decrease in serum sodium and a prolonged increase in serum potassium concentrations, whereas administration of hypertonic saline produced an increase in serum sodium and a transient decrease in serum potassium concentrations. Overall, mannitol produced a greater increase in blood lactate concentrations compared with hypertonic saline (P<0.01). In cerebrospinal fluid, mannitol resulted in significantly greater lactate concentrations compared to hypertonic saline (P<0.01), however, there was no difference in cerebrospinal fluid lactate concentration between groups when considering only non-SAH patients. The authors attributed the serum hyperlactemia observed after mannitol to systemic hypovolemia (ie, greater urine output observed in this group during the first 3 h). The authors concluded that, “hypertonic saline may be recommended as a safe alternative to mannitol for intraoperative brain debulking in patients with and without SAH, especially in hemodynamically unstable patients and/or when excessive fluid shifting should be avoided.”

Analgesia

Pain after neurosurgical procedures is quite common. For example, the incidence of significant pain after craniotomy can be as high as 40% to 80%.26,27 Gottschalk and Yaster 28 reviewed the current literature dealing with the management of pain after craniotomy. The review addressed both opioid and nonopioid treatment options as well as oral, transmucosal, intranasal, and transdermal options.

Recent research suggests that postoperative pain is more severe after infratentorial (vs. supratentorial) craniotomy.29 Specifically, Gottschalk et al 29 reported that in 187 patients undergoing craniotomy, the overall incidence of moderate-to-severe pain (defined as a VAPS of >=4 on a scale of 0 to 10) was 69%. Adult patients underwent supratentorial (N=129) and infratentorial surgery (N=58). Compared with those who had supratentorial surgery, VAPSs during the first postoperative day were significantly higher in those who underwent infratentorial craniotomy at both rest (VAPSs=4.9±2.2 and 3.8±2.6 for infratentorial and supratentorial craniotomy, respectively; P=0.015) and with movement (VAPSs=6.3±2.6 and 4.5±2.7 for infratentorial and supratentorial craniotomy, respectively; P<0.001).

Sedation with short-acting opioids is a common means to achieve comfort in patients in the neurosurgical intensive care unit, however, use of opioids may sometimes decrease blood pressure, necessitating increased vasopressor requirements, and contribute to ileus. Because of its effect on cerebral metabolic rate and ICP, ketamine is often

avoided. Schmittner et al 30 compared the use of S(+)-ketamine (a single enantiomer of ketamine that is a component of the traditionally administered racemic mixture) with fentanyl in 24 patients with either severe TBI (Glasgow Coma Scale <9) or aneurysmal SAH (Hunt and Hess score >1). Prior research has suggested that S(+)-ketamine may have a preferable pharmacologic profile to the racemic mixture.31 All patients received sedation with methohexitone (initial bolus of 1.5 mg/kg followed by a 3 mg/kg/h infusion) and either fentanyl or S(+)-ketamine, both administered as a bolus [3 mcg/kg for fentanyl (N=12) and 0.5 mg/kg for S(+)-ketamine (N=12)] followed by an infusion titrated to BIS of 30 to 50 and a Ramsay Sedation score of <6. The authors found no difference in average daily ICP or cerebral perfusion pressure (Table 1), average norepinephrine requirements to maintain a cerebral perfusion pressure >60 mm Hg [3.6±5.1 mcg/kg/h vs. 12.8±18.4 mcg/kg/h for S(+)-ketamine and fentanyl, respectively; P>0.05], or time to first defecation [43.5±46.0 h vs. 40.9±22.9 h for S(+)-ketamine and fentanyl, respectively; P=0.578]. Although the authors conclude that “S(+)-ketamine does not increase ICP and … its use in neurosurgical patients should not be discouraged on the basis of ICP-related concerns,” their research, described as a “pilot study,” contained a small number of subjects, and —although the authors reported no statistically significant differences between treatment groups—there was a persistent numerical trend for S(+)-ketamine–treated patients to have higher ICP values. On the basis of these concerns, no actual practice changes are warranted until further research, with a larger number of patients and greater statistical power, is conducted.

TABLE 1. Cerebral Hemodynamics After Fentanyl Versus S(+)-KetamineEach parameter reported as mean+SD.Data represent averages of hourly measurements for all patients per group each day.P>0.05 for all comparisons of fentanyl and S(+)-ketamine between groups for each parameter.From J Neurosurg Anesth. 2005;19:257–262 with permission.

Preoperatively administered gabapentin is effective for reducing postoperative pain after a variety of surgical procedures. With regard to neurosurgical procedures, in 2005, Pandey et al 32 reported that gabapentin reduced postoperative pain after spine surgery. Currently, Prabhakar et al 33 evaluated the analgesic effect of preoperatively administered oral gabapentin after brachial plexus surgery. Twenty patients were randomized to receive either placebo or 800-mg oral gabapentin 2 hours before surgery. Fentanyl boluses were administered intraoperatively when the heart rate increased by 20% above baseline values. Postoperative analgesia was provided via intravenous ketorolac. The authors demonstrated a significant decrease in intraoperative fentanyl requirements [median dose was 238 mcg (range: 100 to 400 mcg) vs. 200 mcg (range: 100 to 225 mcg) for placebo and gabapentin, respectively; P=0.03] and median number of ketorolac doses requested during the first 24 hours

postoperatively (2.5 vs. 0, range: 0 to 4 vs. 0 to 3, for placebo and gabapentin groups, respectively; P=0.004). They also reported no difference in average blood pressure and heart rate postoperatively between groups for up to 24 hours, and no side effects were attributed to gabapentin. Of note, it is unclear from the manuscript why a single dose of 800 mg was chosen as, based on data from other types of surgical procedures, lesser doses (ie, 600 mg) may also provide significant analgesic effects yet may be less costly.

Preincisional infiltration of the operative site with local anesthetic solution containing epinephrine used to reduce pain may also reduce hemodynamic responses to incision and provide some element of hemostasis during craniotomy. Yang et al 34 randomized 120 adult patients undergoing craniotomy to receive 16 mL of 1% lidocaine solution containing either 0, 2.5, 5, or 10 mcg/mL epinephrine, infiltrated before surgical incision. No change in heart rate or mean arterial blood pressure was noted after the injection of lidocaine alone. Patients who received epinephrine had a short-lived significant decrease in mean arterial blood pressure and a significant increase in heart rate (Fig. 1). Of note, the mean arterial blood pressure in 7 patients who received epinephrine decreased to less than 50 mm Hg. Data from this investigation also suggested reduced bleeding immediately after incision, but this was based on a rating scale that only measured the degree of hemostasis after incision. The authors attributed these hemodynamic changes to [beta]2-adrenergic receptor agonism by epinephrine. Systemic absorption of epinephrine after scalp infiltration is probably slow enough, even at the 3 doses used in this investigation, to avoid [alpha]1-receptor–mediated vasoconstriction as seen when epinephrine-containing solutions are injected in other locations, such as the nasal mucosa.35 Yang et al 36 also showed that both the decrease in blood pressure and increase in mean arterial pressure after infiltration of the scalp with epinephrine-containing local anesthetic solution can be attenuated by use of a lighter state of general anesthesia.

FIGURE 1. Changes in mean arterial blood pressure (A) and heart rate (B) after scalp infiltration with 16-mL lidocaine solution containing either 2.5 mcg/mL (group 1), 5.0 mcg/mL (group 2), 10 mcg/mL (group 3), or 0 mcg/mL (group 4) of epinephrine. [sharp]P<0.05 and [sharp][sharp]P<0.001 when compared with baseline intragroup and *P<0.05 and **P<0.001 when compared with group 4 at the same timepoint. From J Neurosurg Anesthiol. 2007;19:31–37 with permission.

SAH

In 2007, Priebe 37 published an excellent review of perioperative anesthesia management for SAH patients. The article addressed preoperative, intraoperative, and postoperative management as well as common neurologic and medical complications observed after SAH. Additionally, Smith 38 reviewed the intensive care management of patients with SAH, including diagnosis, prevention, and treatment options for vasospasm, cerebral protection, use of antithrombotic agents, and the diagnosis and management of common medical complications. Regarding medical complications after SAH, we refer interested readers to 2 recent review articles: Sugrue et al 39 focused on cardiac complications after SAH, with specific emphasis placed on the stunned myocardium, and Baumann et al 40 reviewed the epidemiology, pathophysiology, diagnosis, and treatment options for neurogenic pulmonary edema.

Cognitive Function After SAH

After SAH, the incidence of cognitive impairment exceeds that of persistent impairment of gross neurologic function. Furthermore, cognitive impairment may exist even in those patients considered to have a good outcome.41,42 The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST),43,44 compared intraoperative mild hypothermia versus normothermia in patients with SAH undergoing cerebral aneurysm clipping. End points were both gross and cognitive function at 3 months after surgery. Using a subset of IHAST patients, Samra et al 45 evaluated long-term (>6 mo) cognitive function in the Cognitive Function after Aneurysm Surgery Trial (CFAAST). Cognitive function was assessed, in addition to 3-month postsurgery as reported in the original IHAST manuscript,44 at both 9 and 15 months postsurgery in 152 subjects who had a good recovery (ie, Glasgow Outcome Score of 1 to 3 at 6-mo postsurgical clipping). Similar to prior studies noted above, Samra et al reported that cognitive dysfunction was common after SAH, with 36%, 26%, and 23% of subjects demonstrating impairment of global cognitive function 3, 9, and 15 months postsurgery, respectively. The authors reported that global cognitive function improved during the first 9 months after surgery, however, little improvement was noted after 9 months. Long-term cognitive function was not affected by the intraoperative use of hypothermia nor the anatomic location of the aneurysm (anterior communicating artery vs. others). The latter is of interest as altered cognition may be associated with clipping of aneurysms located on the anterior communicating artery.46,47

Haug et al 48 reported on the cognitive function of 32 patients with SAH and subsequent aneurysm treatment (11 clipping and 21 coiling) at 3, 6, and 12 months posttreatment. Unlike the CFAAST trial, which reported a score reflecting global cognitive function in patients with a good outcome, Haug et al study evaluated changes in various metrics of cognition among patients with all grades of SAH. Of note, 72% of their subjects had a Hunt/Hess score of 1 or 2 before treatment, denoting a mild degree of SAH. As with CFAAST, there was a general improvement of cognitive function over time. When tests in specific categories were compared with normative data, patients seemed to regain visual/spatial abilities (such as that tested by the Rey-Osterreith Complex Figure test) and psychomotor functions (ie, using tests of general cerebral efficiency such as the Color-Word Interference Test) before verbal abilities [such as those tested by the color learning and both short and long-delay free recall California Verbal Learning Test-Second Edition (CVLT-II) tests]. The authors suggest that their findings may, in part, be due to retest effects and will require additional formal study. Furthermore, the authors found that cognitive performance was significantly correlated with baseline Hunt/Hess and Glasgow Coma Score, Fisher grade, need for cerebrospinal fluid drainage, and duration of mechanical ventilatory requirements. Factors found not to be associated with cognitive performance were mode of treatment (clipping vs. coiling), postprocedural ventricular size, or either the development of vasospasm or the presence of new low-attenuating regions on computerized tomographic scans. The authors discussed at length the specific associations they observed or lack of associations they expected. However, given the small number of patients included in this investigation and the diversity of their disease and treatments, the probability of type II statistical errors should also be considered in reference to nonsignificant associations.

In another small-scale study designed at assess cognitive function after SAH in 23 patients, Frazer et al 49 compared cognitive abilities at 2 weeks and 6 months in those who underwent clipping (N=12) versus coiling (N=11). At 2 weeks postprocedure, those who underwent clipping did better only on tests of verbal recall; however, when the test scores were corrected for premorbid scores on the National Adult Reading Test, patients who had coiling performed better on the Paired Associate Learning test (a test of memory). At 6 months, those who underwent clipping performed better on tests of intelligence, perception, and executive functions. However, after correction for premorbid National Adult Reading Scores, those who had clipping performed better only on tests of general intelligence. As with the 2 investigations discussed above, there was significant improvement of cognitive abilities over time. The authors conclude that at the early timepoint, coiled patients perform better because they are spared the neurosurgical intervention. The authors do not describe the timepoint at which the “pre-morbid” National Adult Reading Scores were obtained. It seems unlikely that these tests were administered before SAH; if obtained after SAH, they were probably unreliable as a metric of standardization between groups. The authors, therefore, base conclusions on data corrected for National Adult Reading Test Scores, which additionally may be unreliable. As with the Haug et al investigation, given the small sample size, the possibility of type II statistical errors in this investigation should be considered.

Glycemic Control in the Setting of SAH

Outcome after SAH is generally very poor with approximately 25% of patients dying from the initial hemorrhage or later complications. Less than half of those who survive have a good recovery and are able to return to a prehemorrhage level of function.50 Hyperglycemia in the setting of cerebral ischemia is known to exacerbate the extent of injury.51 Also, a variety of studies have demonstrated that hyperglycemia worsens overall outcome in critically ill patients and leads to an increased risk of infections.52–55 It was unknown whether strict glycemic control after SAH leads to improved outcome. Bilotta et al 56 randomized patients who experienced SAH, in whom clipping was the planned method of aneurysm treatment, to either intensive (target blood glucose concentration=80 to 120 mg/dL) or conventional (target blood glucose concentration=80 to 220) glycemic control. The primary outcome measure was rate of all infections and secondary outcome measures were rate of vasospasm as well as both modified Rankin score and mortality rate at 6 months posthemorrhage. Thirty-eight patients were randomized to conventional therapy and 40 were randomized to the intensive protocol. Overall, 10% of patients had a history of diabetes mellitus (equally distributed among both groups) and 58% of patients were hyperglycemic (blood glucose concentration >120 mg/dL) upon hospital admission. The authors found an increased incidence of infectious complications in those who received conventional management (42%) compared with those who received intensive glucose management (27%) (P>0.001). However, the authors found no differences in: (1) overall mortality (18% for conventional vs. 15% for intensive, P=0.9), (2) the incidence of clinical vasospasm (32% for conventional vs. 28% for intensive, P=0.9), or (3) the incidence of poor outcome, defined as a modified Rankin score of 4 to 6 (58% for conventional vs. 53% for intensive, P=0.7). It is important to note that this investigation was powered to detect differences in infection rates between groups, and it may have been underpowered to detect differences in secondary outcomes.

Experimental Markers of Injury After SAH

In recent years, much effort has been placed on identifying laboratory-based tests that could help predict outcome or complications in patients with SAH. A summary of data from investigations published in 2007 that explored various biologic markers and correlated them with outcome are found in Table 2.57–62 In general, the results of these studies, although interesting, should be viewed as preliminary. These studies tend to have small sample sizes and poor positive predictive values (ie, R2). As such, they are better guides to future research than prognosticators of clinical outcome in SAH patients.

TABLE 2. 2007 Investigations Dealing With Potential Laboratory Markers of Outcome After SAHCSF indicates cerebrospinal fluid; GFAP, glial fibrillary acidic protein; GOS, Glasgow Outcome Score; IL-6, interleukin-6.

Cerebral Vasospasm

Cerebral vasospasm can be a devastating complication after SAH. Although the incidence depends on the means of detection (ie, symptomatic vasospasm vs. angiographically detected vasospasm), 17% to 70% of patients who suffer SAH will develop vasospasm,63–65 and vasospasm is a major cause of morbidity and mortality after SAH. A variety of factors such as time after SAH, the amount of blood in the basal cisterns, and baseline neurologic status are all thought to correlate with the risk of developing cerebral vasospasm.

In the past, surgical clipping was the mainstay of treatment for intracranial aneurysms, however, in recent years, interventional radiology techniques (such as occlusion of the aneurysm with metal coils) have come into practice. Some prior investigations suggested that as intracranial clot can be removed at the time of surgical clipping, clipping may be associated with a lower incidence of vasospasm after SAH and treatment.66,67 de Oliveira et al 68 performed a meta-analysis to identify the incidence of vasospasm in patients undergoing surgical aneurysm clipping versus coiling. Nine manuscripts were reviewed: 4 retrospective, 4 prospective, and 1 which was retrospective then became prospective. The authors found no difference between the incidence of symptomatic vasospasm (pooled RR=1.21, 95% CI=0.99-1.48 based on 1355 patients from 6 investigations) or pooled symptomatic and angiographic vasospasm (pooled RR=1.10, 95% CI=0.93-1.31 based on 807 patients derived from 2 investigations) developing after clipping versus coiling. Of note, an RR>1 denotes an observed increase in incidence of vasospasm in the coiling group. Also, based on 913 patients pooled from 4 investigations, there was no difference in the incidence of postprocedural ischemic infarcts between the clipping and coiling groups (pooled RR=0.81, 95% CI=0.59-1.10).

One permanent, and often devastating, sequelae of vasospasm is cerebral infarction. Fergusen et al, performed a post hoc analysis from the database of the tirilazad study, 69–72 which was a randomized, placebo-controlled trial to investigate the effect of the drug tirilazad, an antioxidant steroid devoid of an effect on glucose metabolism, on outcome after SAH.73 (Of note, tirilazad was found to have no significant effect on the outcome compared with placebo.) Their goal was 2-fold: (1) to determine the effect of cerebral infarcts on the outcome after SAH and (2) to determine whether any factors are associated with an increased risk for the development of infarctions. Seven hundred and seven of 2741 (26%) patients had radiographic evidence of at least 1 cerebral infarct at 6 weeks posthemorrhage; this is consistent with other data.74 A variety of factors were found to be associated with poor outcome (defined as a Glasgow Outcome Score of severe disability, vegetative state, or death) at 3 months posthemorrhage; however, the presence of a cerebral infarct had the strongest association with poor outcome [odds ratio (OR)=5.38 (95% CI=4.24-6.82)]. Factors found to be significantly associated with the development of a cerebral infarct were increased age, a premorbid history of hypertension or diabetes, poor neurologic score on admission (as measured by the World Federation of Neurological Surgeons Scale), larger aneurysm size, use of therapeutic hypertension, the development of vasospasm, and hyperthermia measured 8 days posthemorrhage. Of note, this investigation only included patients who underwent surgical clipping of their aneurysms. Also, the specific etiologies of each infarction were not investigated nor reported, and it is likely that vasospasm was not the cause of all of the infarctions reported in this investigation.

In the past, vasospasm was thought to be the primary contributor to the development of cerebral infarction after SAH, however, newer evidence suggests that autoregulatory failure may partially contribute to the development of this devastating complication.75,76 Brain tissue oxygenation monitoring, which measures the partial pressure of oxygen in brain parenchyma, is reported to detect changes in cerebral autoregulation.77 The technique relies on the correlation between cerebral perfusion pressure and brain tissue oxygen partial pressure. If autoregulation of cerebral blood flow is intact, it is assumed that there is little correlation between cerebral perfusion pressure and brain tissue oxygen partial pressure (ie, the correlation coefficient would be approximately 0). If cerebral blood flow is entirely perfusion pressure-dependent, one would expect a strong correlation between cerebral perfusion pressure and brain tissue oxygen content (ie, the correlation coefficient would be approximately 1). Jaeger et al 78 implanted brain tissue content monitoring electrodes (Licox CC1.SB, Integra Neurosciences Inc) into the frontal white matter of 67 patients with poor grade aneurysmal SAH. The frontal white matter was used independent of the location of the ruptured aneurysm. Both cerebral perfusion pressure and the cerebral partial pressure of oxygen were continuously monitored for an average of 7.4 days and patients were prospectively followed for the

development of cerebral infarction (as evident on computerized tomographic scans of the head). Twenty of the sixty-seven patients developed infarcts. Although the authors found no difference in the average partial pressure of oxygen between groups (24±6 mm Hg vs. 21±5 mm Hg for no infarct vs. infarct groups, respectively, P=0.06), patients with subsequent infarction had a higher correlation coefficient between cerebral perfusion pressure and the partial pressure of oxygen in the frontal white matter (0.43±0.09) than those without infarcts (0.23±0.14) (P<<0.001). When comparing daily data, differences in the correlation coefficient were not significant until post-SAH day 5 (Fig. 2). These data, therefore, support the prior finding that dysfunctional cerebral autoregulation may be a risk factor for the development of infarcts. However, as alterations of autoregulation may be a local phenomena, consideration should be given to stratifying these data with respect to those patients in whom oxygen monitoring was carried out in the territory supplied by the artery on which the ruptured aneurysm was located. Future research with larger samples may enable estimation of an optimized cutoff number for the correlation coefficient, which would predict the development of infarcts.

FIGURE 2. Time course of changes in the correlation coefficient in patients after SAH. The black line indicates those without infarction and the gray line indicates those with cerebral infarction. P values from the Mann-Whitney U test for each day are found above the x-axis. From Stroke. 2007;38:981–986 with permission.

Given the presence of an inflammatory component in the pathophysiology of vasospasm, Belen et al 79 evaluated the use of the anti-inflammatory drug leflunomide on the development of vasospasm in a rabbit model of SAH. Twenty-two animals were anesthetized and randomized to one of the 4 groups: (1) control (no SAH/no drug, n=5), (2) SAH/no drug (n=5), (3) SAH plus oral leflunomide (n=7), and (4) SAH plus oral vehicle (n=5). Animals in groups 3 and 4 received either leflunomide 2 mg/kg or vehicle via a nasogastric tube 12 hours after the induction of SAH. The animals were killed 72 hours after SAH and the basilar arteries were examined histologically. Average basilar artery diameter was significantly greater in the animals that received leflunomide (0.26±0.08 mm2) compared with those in the SAH/no drug group (0.09±0.01 mm2; P<0.01) and the SAH plus oral vehicle group (0.12±0.02 mm2; P<0.01), but not different from the no SAH/no drug control group (0.27±0.07 mm2; P>0.05). Also, average basilar artery wall thickness was attenuated by the administration of leflunomide after SAH (27±10 µm) compared with those in the SAH/no drug 5±17 µm; P<0.01) and SAH plus vehicle groups (35±16 µm; P<0.01). Basilar artery wall thickness in the no SAH/no drug control group was 23±9 µm. This result shows promise that another treatment modality may eventually be available for vasospasm. It will be exciting to see the results of future studies that assess functional outcome after administration of leflunomide.

The mainstay of management of patients with vasospasm includes prophylactic nimodipine, “triple-H” therapy (ie, hypertension, hypervolemia, and hemodilution), angioplasty, and intra-arterial vasodilators. One investigation that

caught the attention of many was a small prospective trial in which 80 patients were randomized to receive either placebo or pravastatin after SAH.80 Statins were hypothesized to attenuate vasospasm in part because of their ability to induce nitric oxide synthase, a potent vasodilator. Tseng et al 81 reported that pravastatin led to a significant reduction in vasospasm as measured by transcranial Doppler sonography, delayed ischemic neurologic deficits, impaired cerebral autoregulation, and mortality. In a post hoc analysis of a database from their prior study, Tseng et al evaluated other end points: hospital length of stay, need for triple-H therapy, and outcome measured by a binary modified Rankin score (1 to 2=favorable, 3 to 6=unfavorable) at 6 months posthemorrhage.81 In 80 patients, who were randomized to receive either 40-mg pravastatin or placebo for up to 14 days posthemorrhage (65% of whom underwent craniotomy and surgical clipping as their primary treatment), despite a lack of difference in length of hospital stay, few patients in the pravastatin group required triple-H therapy (17.5% vs. 37.5% for placebo; P=0.045). They also discovered that those who received pravastatin had a lesser chance of a bad outcome at hospital discharge (OR=0.27, 95% CI=0.08-0.95; P=0.014), but not at 6 months (OR=0.29, 95% CI=0.08-1.07; P=0.063). Furthermore, risk of mortality was reduced in those who received pravastatin (OR=0.12, 95% CI=0.02-0.69; P=0.018). One must keep in mind that this is a small study not powered to detect differences in these secondary outcome variables.

Calcium channel antagonists have an important role in the prevention and treatment of vasospasm. Nimodipine is currently the first-line drug for the prevention of vasospasm, and nicardipine and verapamil, usually administered intra-arterially, can be used as rescue treatment for patients who have developed vasospasm that does not respond to conservative treatment. Lavine et al 82 characterized the cerebral hemodynamic effects of both nicardipine and verapamil in both normal rabbits and those in which experimental cerebral vasospasm was induced via the intracranial administration of interleukin-1. Cerebral blood flow was estimated using laser Doppler velocimetry. In 7 control rabbits (ie, without vasospasm), escalating doses of 0.0001, 0.001, 0.01, and 0.1 mg of verapamil and 0.0001, 0.001, and 0.01 mg of nicardipine were injected into the internal carotid artery. At equivalent milligram doses, nicardipine resulted in significantly greater increases in laser Doppler signal, thus indicating greater increases in cerebral blood flow. Doses of 0.01 mg of verapamil and nicardipine resulted in a 40% and 85% increase, respectively, in laser Doppler signal compared with baseline (ie, before injection of drug). The investigators then applied 5×10-3 moles of interleukin-1 topically to cerebral arteries and, using videomicroscopy, measured the changes in pial arterial diameter via a cranial window. Intra-arterial administration of both verapamil (0.0001, 0.001, 0.01, 0.1, and 1 mg) and nicardipine (0.0001, 0.001, 0.01, 0.1, and 1 mg) resulted in dose-dependent increases in pial vessel diameter after the administration of interleukin-1. However, with any dose of verapamil, vessel diameter never increased enough to return to baseline (ie, before the administration of interleukin-1). Nicardipine at doses of 0.1 and 1 mg resulted in vessel diameters that were greater than baseline. The authors concluded that nicardipine is superior to verapamil at reversing experimental vasospasm in this rabbit model. They also noted greater phenylephrine requirements during testing with nicardipine than with verapamil, owing to more severe systemic hypotension. The authors discuss the fact that this model of vasospasm may not truly represent that associated with SAH. The authors do not address in their discussion the observation that very little change in laser Doppler signal occurred upon the administration of interleukin-1. One would expect an increase in laser Doppler signal with the institution of cerebral vasospasm, but this was not observed.

Barth et al 83 evaluated the use of nicardipine pellets, applied directly to cerebral arteries at the time of craniotomy for aneurysm clipping, on the incidence of vasospasm after SAH. Thirty-two patients scheduled for aneurysm clipping were randomized to receive either (1) implantation of ten 2×10-mm polymer rods each containing 4 mg of nicardipine on vessels likely to develop vasospasm (depending on the location of the ruptured aneurysm) after irrigation of blood from the basal cisterns (N=16) or (2) irrigation of the basal cisterns without rod implantation (N=16). Subjects did not receive prophylactic nimodipine. Vasospasm was assessed at 8 days post-SAH via angiography. Vasospasm was defined as a >=33% decrease in the diameter of any vessel segment. Outcome at 1 year was assessed via the modified Rankin score (0 to 2=good outcome) and the National Institutes of Health Stroke Scale (0 to 4=good outcome). The incidence of vasospasm was reduced from 73% in the control group to 7% in the group that received nicardipine-containing rods (P<0.05). Similarly, mortality was reduced from 38% to 6% by nicardipine treatment (P=0.042). When assessing 1-year outcome with the modified Rankin score, the incidence of a good outcome was 38.5% in the control group versus 85% with nicardipine treatment (P=0.001). When outcome was assessed using the National Institutes of Health Stroke Scale, good outcome increased from

71% of control patients to 100% of nicardipine-treated patients (P=0.001). The authors attributed no adverse events to the nicardipine rods and concluded that treatment was very effective at reducing the incidence of vasospasm after SAH. Their analysis of long-term outcome, however, did not account for the several living patients who were unwilling to participate in the 1-year assessment of National Institutes of Health Stroke Scale, or the single nicardipine-treated patient who died. Thus, despite these limitations, the authors reported that 100% of patients treated with nicardipine rods had a good outcome at 1 year on the basis of the National Institutes of Health Stroke Scale.

Deep Hypothermic Circulatory Arrest

The use of deep hypothermic circulatory arrest to facilitate cerebral aneurysm clipping has probably decreased in recent years owing to advances in interventional radiologic methods to treat cerebral aneurysms. However, deep hypothermic arrest may still be required in select cases owing to patient factors or aneurysm anatomy. Levati et al 84 described their practice and outcome associated with deep hypothermic circulatory arrest in 12 patients (2 with large and 10 with giant cerebral aneurysms) who underwent surgical treatment of their aneurysms. Eleven received femoral/femoral closed-chest bypass and 1 patient required open-chest bypass owing to aortic valve insufficiency. Average anesthesia duration was 13.5±1.1 hours (range: 8.3 to 17.2 h). The mean duration of cardiopulmonary bypass and circulatory arrest were 156±23 minutes (range: 125 to 190 min) and 26.5±13.9 minutes (range: 9 to 54 min), respectively. No adverse intraoperative or postoperative cardiac events were reported. Outcome was good (Glasgow Outcome Score=no or mild disability) in 9 of the 12 patients and no deaths were noted. Of note, the authors of this investigation were very thorough in describing intraoperative patient management as this article may prove useful to those readers interested in having a reference for anesthetic techniques used for this rarely performed procedure.

Mack et al 85 reported on 66 patients at Columbia University College of Physicians and Surgeons, New York, NY who underwent deep hypothermic circulatory arrest for the treatment of cerebral aneurysms. They reported 7 deaths, 2 attributed to the bypass procedure (1 had a ruptured aortic root and the other suffered postoperative cardiac tamponade) and 5 owing to neurologic complications. Forty-four patients had a good outcome (Glasgow Outcome Score=no disability to moderate disability) and poor outcome was associated with increased age and duration of hypothermic circulatory arrest. It was unclear whether cardiac bypass was performed via open-chest or closed-chest (ie, femoral artery and femoral vein) cannulation. It is possible that the higher incidence of both poor outcome and mortality in the Mack et al investigation compared with that reported by Levati et al 84 may be owing to the latter's greater use of closed-chest cardiopulmonary bypass.

TBI

TBI is a major cause of morbidity and mortality. Annually, in the United States alone, approximately 2 million injuries result in about 50,000 deaths.86–89 In 2007, The British Journal of Anaesthesia published a series of review articles that comprehensively addressed the perioperative anesthetic care of patients with TBI. Topics reviewed include the pathophysiology of TBI,90 impact of genetic factors on outcome,91 assessment and early management of TBI,92 as well as monitoring,93 imaging,94 and intensive care management.95

Guidelines

In 2007, the Brain Trauma Foundation and their associated Center for Guidelines Management published evidence-based guidelines for the management of patients with TBI. The article described the process used to develop these guidelines (ie, literature review, criteria used for including or excluding data).96 We have provided a summary of these recommendations in Table 3. They are stratified based on the quality of the data used to support each recommendation. Specifically, level 1 recommendations are derived from credible, randomized-controlled trials, whereas level 2 recommendations were based on data derived from either moderate-quality randomized-controlled trials or good-quality cohort or case-control studies. Finally, level 3 recommendations were based on poor-quality randomized-controlled trials, moderate or poor-quality cohort or case-control studies, or case series, databases, or patient registries.97

TABLE 3. Brain Trauma Foundation Traumatic Brain Injury RecommendationsLevel 1 evidence=good quality randomized-controlled trial.Level 2 evidence=moderate quality randomized-controlled trial or good quality case-control or cohort study.Level 3 evidence=poor quality randomized-controlled trial, moderate or poor quality case-control or cohort study, or case series, databases, or registries.CPP indicates cerebral perfusion pressureAdapted from the text of J Neurotrauma. 2007;24(suppl 1):S1–S106.

International Mission for Prognosis and Clinical Trial Database

Also in 2007, the Journal of Neurotrauma dedicated an issue to description of the organization and results of an initial analysis of the International Mission for Prognosis and Clinical Trial (IMPACT) database of TBI. 98–108 The IMPACT database consists of pooled TBI data on 9502 patients from 8 randomized-controlled trials 109–114 and 3 observational studies.115–117 Of note, the database included patient data from 2 randomized-controlled trials for which the full results have not yet been published (ie, the North American Tirilazad Trial and the Saphir Trial, which were designed to assess the efficacy of tirilazad and the competitive N-methyl-D-aspartate antagonist D-CPP-ene, respectively, in patients with TBI). Overall IMPACT outcome was typically assessed at 6 months postinjury using the Glasgow Outcome Score; however, this sometimes required imputation from 3-month Glasgow Outcome Scores if 6-month scores were not recorded. In the univariate analysis, Glasgow Outcome Scores were dichotomized in a variety of ways [ie, dead vs. alive, dead or vegetative state vs. conscious survival, good recovery vs. less-than-good recovery, and favorable (good recovery or moderate disability) vs. unfavorable (severe disability, vegetative state, or death) recovery] and via proportional odds models over the range of Glasgow Outcome Scores.104 Outcome results reported in this review are derived from the proportional odds models.

Mushkudiani et al 107 evaluated the demographics of the IMPACT patients and outcome. They discovered that poor outcome correlated with increasing age [OR=2.14 (CI=2.00-2.28), on the basis of the shift in outcome between the 75th and 25th percentile for age, although this analysis did not include children <14 y], and black race [OR=1.30 (CI=1.09-1.56) compared with white race], but not sex. Furthermore, those with higher education (>12 y of school) had better outcome than those with <9 y of education [OR=0.70 (CI=0.52-0.94)]. The associations between outcome versus education or race were still statistically significant after correcting for other factors thought to influence outcome (ie, age, motor scores, and pupil reactivity).

Butcher et al 99 examined the relationship between cause of injury in the IMPACT database and outcome. Cause of injury was stratified into motor vehicle accidents, assault, falls, work-related injuries, sports injuries, and other miscellaneous causes. Injuries from motor vehicle accidents [OR=0.66 (CI=0.60-0.73)], assaults [OR=0.66 (CI=0.52-0.84)], and sports-related injuries [OR=0.45 (CI=0.28-0.71)], but not work-related injuries [OR=0.88 (CI=0.68-1.14)] had a better outcome than those who experienced falls. However, after the correction for age, these relationships failed to maintain significance, simply because falls were associated with older age.

McHugh et al 105 investigated secondary insults before, or at, hospital admission in IMPACT patients. Hypoxia (PaO2<60 mm Hg), hypotension (systolic blood pressure <90 mm Hg), and hypothermia (body temperature <35°C) were all independently associated with poor outcome {[OR=2.1 (CI=1.7-2.6)], [OR=2.7 (CI=2.-3.4)], and [OR=2.2

(CI=1.6-3.2)] for hypoxia, hypotension, and hypothermia, respectively}. These relationships with outcome were still statistically significant after correction for age, motor score, and pupil reactivity. These discoveries suggest that the quality of prehospital care probably has some bearing on long-term outcome. Butcher et al 98 further evaluated the relationship between admission blood pressure and outcome. Univariate modeling and spline plots (ie, a polynomial-based technique used to smooth data) demonstrated a U-shaped curve between outcome and both systolic and mean arterial pressure obtained upon admission to the hospital, with the most favorable outcome occurring at a systolic blood pressure of 135 mm Hg and a mean arterial pressure of 90 mm Hg (Fig. 3). When both systolic and mean arterial pressures where categorized as trichotomous variables (ie, for systolic blood pressure <120 mm Hg, 120 to 150 mm Hg, and >150 mm Hg; for mean arterial pressure <85 mm Hg, 85 to 110 mm Hg, and >110 mm Hg), those with both admission systolic and mean blood pressures in the upper and lower tertiles had significantly greater odds of a worse outcome at 6 months compared with those in the midtertile as assessed by proportional odds modeling. However, when the nature of the relationship between systolic blood pressure and outcome was assessed by using spline functions, and correcting for age, motor score, and pupil reactivity, the association between increased systolic blood pressure and poor outcome largely disappears. The results of this study, therefore, clearly support the avoidance of hypotension, and to a much lesser extent, the avoidance of hypertension.

FIGURE 3. Spline plots demonstrating the relationship between the probability of a poor outcome at 6 months and both systolic blood pressure (A) and mean arterial pressure (B) upon hospital admission after TBI. The lowest (first) line represents the probability of mortality; the second line, combination of mortality and persistent vegetative state; the third line, unfavorable outcome (ie, mortality, persistent vegetative state, and severe disability); and the fourth line, probability of less than good outcome. The distribution of blood pressures are indicated by the bars just above the x-axis in each graph. From J Neurotrauma. 2007;24:294–302 with permission.

In another analysis of the IMPACT database, Van Beek et al 108 examined the relationship between admission laboratory values and outcome based on both spline functions and proportional odds models (Fig. 4). Using proportional odds modeling and comparing outcome with 75th percentile value to that of the 25th percentile value, elevated glucose [OR=1.68 (CI=1.54-1.83)], low blood pH [OR=0.80 (CI=0.74-0.88)], low platelet concentration [OR=0.70 (CI=0.62-0.80)], and low hemoglobin concentration [OR=0.69 (CI=0.60-0.78)] were associated with

poor outcome and these relationships remained significant after correction for age, motor score, and pupil reactivity.

FIGURE 4. Spline function plots demonstrating the relationship between outcome at 6 months postinjury and various laboratory parameters obtained upon hospital admission in patients with traumatic brain injury with probability of a poor outcome depicted on the y-axis. The lowest (first) line represents the probability of mortality; the second line, the combination of mortality and persistent vegetative state; the third line, unfavorable outcome (ie, mortality, persistent vegetative state, and severe disability); and the fourth line the probability of less than good outcome. The distribution of values for each are indicated by the bars just above the x-axis in each graph. From J Neurotrauma. 2007;24:315–328 with permission.

Many of the findings of this initial analysis of the IMPACT database will need further investigation and validation. Also, these findings simply demonstrate associations, not cause-and-effect relationships. Finally, one should be careful in applying these findings to the general care of hospitalized patients with TBI as TBI is a dynamic disease state and may require alterations in management depending on specific patients. Nevertheless, the results of this research are impressive and should generate hypotheses for future investigations.

Fluid Management

As in many other aspects of clinical medicine, there is ongoing debate over fluid choice (ie, crystalloid vs. colloid) in TBI patients. In 2004, the results of the Saline versus Albumin Fluid Evaluation (SAFE) study were published.118 A homogeneous population of intensive care unit patients were randomized to receive either 0.9% saline or albumin solution as their primary fluid replacement. There was no difference between groups with respect to the primary outcome measure, 28-day mortality, or a variety of secondary outcome measures. In this primary investigation, there was a tendency toward increased mortality in trauma patients who were randomized to the albumin group. In 2007, the SAFE study investigators published a post hoc analysis of this same database including only patients with TBI.119 Primary outcome measures were mortality and functional outcome (assessed via the extended Glasgow Outcome Score where a score of 5 to 8=good outcome and 1 to 4=poor outcome) at 24

months postinjury, and imputed results were not used. Outcome data were available for 214 and 206 subjects in the albumin and saline groups, respectively. Overall mortality and incidence of poor outcome was 33.2% and 52.7% for the albumin group and 20.4% and 39.4% for the saline group (P=0.003 and 0.007 for mortality and incidence of a poor outcome, respectively). Therefore, the relative risk of mortality at 24 months after injury was 1.63 times greater (CI=1.17-2.26) after the administration of albumin to patients with TBI. This remained significant even after correction for covariates thought to influence outcome (ie, age >60 y, initial Glasgow Coma Score <9, initial systolic blood pressure <90 mm Hg, and presence of traumatic SAH) with an adjusted OR of death after albumin compared with 0.9% saline of 1.70 (CI=1.03-2.84; P=0.04). Subjects were then further stratified into those with severe (initial Glasgow Coma Score=3 to 8) or moderate (initial Glasgow Coma Score=9 to 12) TBI. Risk of death or poor functional outcome was greater in those with severe TBI after administration of albumin compared with saline [relative risk of mortality =1.88 (CI=1.31-2.70; P<0.001 and relative risk for poor outcome=1.49 (CI=1.15-1.96; P=0.002)], but not in those with moderate TBI [relative risk of mortality=0.74 (CI=0.31-1.79; P=0.50) and relative risk for poor outcome=0.91 (CI=0.68-1.20; P=0.51)]. The authors hypothesized that this dramatic finding was likely related to the exacerbation of cerebral edema by albumin. Such a conclusion is quite speculative because, although initial ICP did not differ between groups (recorded in 69% of study subjects), this research did not document ICP or radiographic evidence of cerebral edema after initiating fluid therapy.

As the brain is a rich source of thromboplastin, an activator of the coagulation cascade, TBI can be associated with the development of coagulopathy,120 which can lead to a variety of secondary complications such as delayed hematoma formation or adult respiratory distress syndrome.121,122 Etemadrezaie et al 123 hypothesized that the prophylactic administration of fresh frozen plasma to patients with TBI might at least partially correct coagulopathy and improve outcome. They prospectively randomized 90 patients with severe TBI (initial Glasgow Coma Score <9) to receive either 0.9% saline (n=44) or fresh frozen plasma (n=46) (10 to 15 mL/kg body weight over 3 to 4 h) after physiologic stabilization after TBI. The groups were well matched except for a higher incidence of both hypotension (systolic blood pressure <90 mm Hg) on admission (27% in plasma group vs. 11% is saline group; P=0.04) and intracerebral hematoma evident upon initial computerized tomogram of the head (36% for plasma vs. 17% for saline; P=0.042). Patients who received fresh frozen plasma had a higher incidence of new intracerebral hematoma (19% for plasma vs. 0% for saline; P=0.002) and a greater 1-month mortality rate (64% for plasma vs. 35% for saline; P=0.006). Although the authors listed the specific causes of the mortalities in each group, the study was too small to draw any statistical conclusions about tendencies for various fatal events to occur in either group. However, the authors reported that overall, 3 of the 90 patients developed disseminated intravascular coagulation (2 in the plasma group vs. 1 in the saline group) and all 3 patients died. The authors hypothesized that the higher mortality and incidence of new intracerebral hematomas may have been owing to an increase in available plasma coagulation factors after the administration of fresh frozen plasma, which possibly led to a higher incidence of microvascular thrombosis. Verification of this hypothesis was beyond the scope of this small investigation, and baseline differences in the treatment groups probably had an impact on the results. Also, empiric administration of fresh frozen plasma exposes patients to the risks of transfusion (ie, transfusion reaction, infection). Hence, unless these data are validated by a larger trial, empiric administration of fresh frozen plasma in this population probably entails more known risks than established benefits.

Laboratory Markers and Outcome After TBI

In recent years, much research has focused on the role of magnesium as a neuroprotectant and its relationship to outcome after brain ischemia or injury.124–128 Using a database of patients with TBI at the Brain Trauma Research Center at the University of Pittsburgh, Stippler et al 129 evaluated the relationship between serum magnesium concentrations and outcome in 216 patients with severe TBI (initial Glasgow Coma Score <9). Those patients with an initial serum magnesium concentration of <1.3 mEq/L were 2.37 (CI=1.18-4.78) times more likely to suffer an unfavorable outcome (6-mo Glasgow Outcome Score of good recovery or moderate disability) than patients with normal serum magnesium (1.3 to 2.1 mEq/L) (P=0.016). Of the 119 patients with initial low magnesium concentrations, magnesium concentrations were not successfully corrected to within the normal range within 24 hours, despite replacement, in 88 patients. Patients in whom initial serum magnesium concentration was low but was successfully corrected had an 11.03 (CI=1.87-68.19) times greater risk of poor outcome at 6 months compared with patients who had a low initial serum magnesium concentration that was not corrected despite

treatment (P=0.008), even after correcting for age, sex, and initial Glasgow Coma Score. Although low serum magnesium concentrations may be a marker for poor outcome after TBI, the authors hypothesized that correction of hypomagnesemia may lead to increased penetration of magnesium via a disrupted blood brain barrier into the central nervous system and disruption of ion pumps or cell membrane integrity. It is interesting to note that another investigation, using data from the magnesium sulfate and acetylsalicylic acid in Subarachnoid Hemorrhage Trial,130 showed that those with increased magnesium concentration (>1.62 mmol/L) had a 4.9 (CI=1.2-19.7) times greater risk of poor outcome than those with magnesium concentrations of 1.10 to 1.28 mmol/L.128 Obviously, further investigation is needed to determine the role and safety profile of magnesium administration in patients with neurologic injury. Until such research is completed, it is appropriate to question whether the administration of magnesium as a “neuroprotectant” to patients with TBI is really a benign practice.

In recent years, a significant amount of research has addressed the role of neuron-specific enolase and S100B proteins as biomarkers of outcome in patients with neurologic injuries such as TBI or intracranial bleeding. Descriptions of these proteins can be found in Table 2. Shore et al 131 investigated changes in these 2 serum biomarkers in the cerebrospinal fluid of children with TBI and their relationship to both initial Glasgow Coma Score after stabilization and 6-month Glasgow Outcome Score. The authors used stored cerebrospinal fluid samples obtained for use in 2 other investigations involving 88 children (mean age 7±5 y, range not reported) who suffered TBI with an initial postresuscitation Glasgow Coma Score <9.132,133 Although the authors discovered a significant overall negative correlation between both neuron-specific enolase and serum S100B concentrations with both initial Glasgow Coma Score (r=-0.49, P<0.0001 for both serum neuron-specific enolase and S100B concentrations) and 6-month Glasgow Outcome Score (r=-0.36, P=0.006 for neuron-specific enolase and r=-0.39, P=0.002 for S100B concentrations), they did not report possible cutoff values that could be used to predict outcome. On gross evaluation of data presented in graphic form in their manuscript, it seems that any chosen cutoff point would probably have a poor sensitivity, specificity, and predicative values for outcome (Fig. 5). Furthermore, they report that the significance in the correlation between both neuron-specific enolase and S100B concentrations disappears when only children <4 y are included in the analysis (Spearman correlation coefficient and P values not reported in the paper).

FIGURE 5. Scatter plots of neuron-specific enolase (NSE) and S100B concentrations stratified by both Glasgow Coma Score (A, C) and Glasgow Outcome Score (B, D). Spearman correlation coefficient (r) and P values are shown for each data set. Glasgow Outcome Score is coded as follows: 1, death; 2, persistent vegetative state; 3, severe disability; 4, moderate disability; 5, good outcome. From J Neurotrauma. 2007;24:75–86 with permission.

Immunodeficiency has been described after TBI 134 and changes in serum interleukin-6 concentrations (a marker of immune system function) have been shown to correlate not only with neurologic outcome but with the development of pneumonia after TBI.135,136 Standard determinations of interleukin-6 concentrations involve an enzyme-linked chemiluminescence immunoassay.137 Schlosser et al 138 report on the use of a simpler lateral-flow immunoassay (Milenia Biotec GmbH, Bad Nauheim, Germany), which incorporates either visually assessed color changes or densitometer determinations to obtain interleukin-6 concentrations at the bedside. Using the gold standard technology to determine serum interleurkin-6 concentrations (Immunolyte, DPC Biermann), a cutoff value of 98 pg/mL had a 67% sensitivity, 94% specificity, and a 91% positive predictive value for the development of pneumonia within 1 week of TBI. A cutoff of 94 pg/mL determined via bedside testing with the lateral-flow immunoassay and densitometry (PicoScan) had a sensitivity of 82%, a 100% specificity, and 100% positive predicative power for pneumonia. Manual colorimetric visual assessments using a cutoff of 300 pg/mL had only 40% sensitivity but a 100% specificity and positive predictive power for pneumonia. Differentiation via visual assessment can only be conducted with 4 possible cutoff values (<100, 100 to 300, 300 to 1000, and >1000 pg/mL). Cutoff values represent optimized sensitivity and specificity. This simple test shows promise and it will be interesting to see whether other outcome measures can be correlated with interleukin-6 concentrations determined in this manner.

CAROTID ENDARTERECTOMYAnesthetic Considerations

Despite the growing practice of nonsurgical treatment for atherosclerotic disease of the carotid artery, carotid endarterectomy still remains a major treatment option for stroke prevention in patients with carotid artery stenosis.

A recent review of anesthetic considerations for carotid endarterectomy can be found in the British Journal of Anaesthesia.139 In this article, Howell 139 reviews the indications for endarterectomy, perioperative complications, data supporting or refuting various monitors of cerebral well-being, and both intraoperative and postoperative patient care considerations.

Anesthetic options for patients having carotid endarterectomy consist of either general or regional anesthesia. Typically, regional anesthesia can be accomplished via superficial or deep blockade of the cervical plexus or a combination of both superficial and deep block. Pandit et al 140 performed a meta-analysis of data from 83 investigations, published between 1974 and 2006, describing complications associated with superficial and deep cervical plexus block. Patients in the Pandit et al analysis were divided into 2 groups depending on whether or not a deep approach was used. In comparing data derived from 2533 superficial blocks to 7558 deep or combined (ie, deep plus superficial) blocks, deep or combined blocks were associated with a greater risk of complications attributed to block placement (0% for superficial, 0.25% for deep or combined; P=0.006) and a greater need to convert to general anesthesia (0.39% for superficial, 2.08% for deep or combined; P<0.0001), but there was no difference in the incidence of serious complications (4.18% for superficial, 4.72% for deep or combined; P=0.27). Common complications associated with block placement were intravascular injection or respiratory distress owing to presumed diaphragmatic or vocal cord paralysis. The most common reasons to convert to general anesthesia were block failure (0% for superficial, 0.9% for deep or combined; P<0.0001), patient anxiety or lack of cooperation (0.36% for superficial vs. 0.87% for deep or combined, P=0.009), insertion of a shunt (overall 0.17%), and direct complications related to the block (overall 0.05%). The most common serious perioperative complications (regardless of the cause) were stroke (2.8% for superficial and 2.5% for deep or combined; P=0.51) and cardiovascular problems (0.20% for superficial and 1.4% for deep or combined; P<0.0001). Pandit et al concluded that superficial cervical plexus block is probably safer than deep cervical plexus block and attribute the lower rate of conversion to general anesthesia to possible better surgical anesthesia provided by the superficial cervical plexus block.

Monitoring for Cerebral Ischemia During Carotid Endarterectomy

Shunt placement during carotid endarterectomy is usually performed on a case-by-case basis. In general, shunt use is associated with an increased risk of postoperative stroke.141 The decision to place a shunt is usually based on evidence of cerebral hypoperfusion, assessed by a variety of monitoring modalities. However, the “gold standard” of monitoring is typically believed to be the development of new neurologic changes in an awake patient. It is currently unknown how various monitoring modalities compare with the awake neurologic examination in terms of their effectiveness and reliability for detecting cerebral hypoperfusion. Moritz et al 142 compared common monitors of cerebral ischemia with the awake neurologic examination in 48 patients having carotid endarterectomy under regional anesthesia. In addition to neurologic assessments, patients had measurement of Doppler sonography of middle cerebral artery blood flow velocity (the minimum velocity after carotid clamping and the percentage decrease in velocity from the preclamp velocity were determined), stump pressure measured 5 to 10 minutes after cross clamping, near infrared spectroscopy assessed at the ipsilateral parietotemporal region of the cranium (both minimum and percentage decrease in regional oxygen saturation were determined), and somatosensory-evoked potentials (via stimulation of the median nerve and detected at C3' and C4' electrode—amplitude decrease of the N20/P25 complex was recorded). Except for a failure of transcranial Doppler sonography in 10 patients (21%) and somatosensory-evoked potentials in 2 patients (4%), all other monitoring modalities were successful. Twelve of the forty-eight patients (25%) developed neurologic changes after carotid occlusion. The effectiveness of each monitoring modality was assessed using receiver-operating characteristics where a graph of each test's true positive rate (y-axis) is plotted for each false positive rate (x-axis). The area under each curve is determined and is proportional to each test's ability to discriminate true from false positive test results. For example, if a test is unable to distinguish between 2 groups (ie, neurologic changes vs. no neurologic changes after clamping), then the area under the curve=0.5. If the test always accurately distinguishes between the 2 groups, the area under the curve=1.0. The authors reported that all methods used to detect cerebral ischemia, compared with the gold standard neurologic assessment, had the ability to distinguish ischemia from nonischemia as no 95% CIs calculated for the area under the received operating characteristics curve contained 0.5 (Fig. 6). They also reported that the percentage decrease in middle cerebral arterial blood flow velocity had the best discrimination (ie, area under the curve=0.973), and

somatosensory-evoked potential monitoring had the worst discrimination (ie, area under the curve=0.749). Although transcranial Doppler sonography was most discriminatory, it was also the most technically unreliable. Although this study presented interesting findings, it had multiple limitations. First, most of these monitoring modalities would typically be used during general anesthesia, as compared with awake neurologic assessments, which would be the preferred monitoring technique during regional anesthesia. The general anesthetic state often has a significant influence on each of these monitoring modalities owing to drug-induced alterations in cerebral blood flow 143 or suppressant effects on evoked potential signals. Furthermore, the most common modality used during general anesthesia, electroencephalography, was not included in this investigation. Finally, the authors measured changes in the amplitude of somatosensory-evoked potential signals and may have had a different result if latency was also assessed.

FIGURE 6. Receiver-operating characteristic curves of the investigated monitoring methods. AUC indicates area under the curve; CI, 95% confidence interval; min, minimum during clamping; NIRS, near-infrared spectroscopy; SEP, somatosensory evoked potentials; TCD, transcranial Doppler sonography; %, relative reduction compared with baseline. From Anesthesiology. 107;2007:563–569 with permission.

NEUROPROTECTION

Perioperative brain injury can occur in a wide variety of circumstances and prompt commencement of the American Heart Association's “A, B, C's” (ie, airway, breathing, and circulation) as the cornerstone of care. In addition to these, benefit may accrue from good general medical care and a variety of both pharmacologic and nonpharmacologic interventions. For a brief, but thorough, review of the neuroprotection literature, we refer the readers to a recent review by Fukuda and Warner.144 For a more focused review of anesthetic agents and their neuroprotective effects, we refer readers to a review by Head and Patel.145 In addition to the standard anesthetics (ie, volatiles, barbiturates, propofol), the authors briefly review the neuroprotective effects of xenon and lidocaine, however, they did not address the reported neuroprotective effects of dexmedetomidine.

Hypothermia

Hypothermia has been used for decades as means of protecting the central nervous system from injury. However, use of hypothermia is not without risks and should, therefore, be limited to clinical circumstances where the beneficial effects on long-term outcome are known to exceed short-term detriment from side effects.

Although the utility of hypothermia is still debated, it is clear that hyperthermia in the setting of neurologic injury is detrimental and should be avoided.146–148 Fever is common in patients with neurologic injury and can result from infectious or noninfectious (ie, hypothalamic dysfunction) causes. Treatment of fever typically involves the use of antipyretic drugs as well as identification and treatment of infectious causes; external-cooling blankets may be used to decrease body temperature in refractory cases. Hinz et al 149 compared the efficacy, and side effects, of an intravascular cooling device with that of a standard therapy with cooling blankets in 26 patients with SAH or TBI and a body temperature of >38.5°C. The CoolGard system (CoolGard, Alsius, CA) used a cooled saline solution that is circulated to an indwelling 8.5-French central venous catheter. There was no difference between the

study groups with respect to length of stay in the intensive care unit or incidence of infections. Patients who received the Cool-Gard therapy, despite receiving significantly less antipyretic drug treatment, spent more time at or below the accepted normothermic target of 36.5°C bladder temperature. However, the cost of Cool-Gard therapy was much higher [39 US $/d (range: 15 to 140 US $/d)] than conventional cooling blanket therapy [5 US $/d (range: 1 to 9 US $/d)] (P<0.001). This research identified no complications from the CoolGard system. This study would have benefitted from more extensive reporting of outcome data, other than intensive care unit length of stay, to determine whether the cost of this new treatment modality was justified.

Hypothermia is reported to attenuate intracranial hypertension,133,150 however, very little is currently known about the impact of hypothermia and rewarming on cerebral hemodynamics, specifically autoregulation of cerebral blood flow. In humans, mild hypothermia has no major adverse effect on autoregulation,151 however, hypothermia and rapid rewarming may adversely affect autoregulation of blood flow.152 In a retrospective analysis of prospectively acquired data, Lavinio et al 153 evaluated the effect of hypothermia on cerebrovascular reactivity in 24 patients with severe TBI and refractory intracranial hypertension. Using the cerebral pressure reactivity index as described earlier in this paper (please see the “vasospasm” subsection in the “SAH” section) to estimate changes in cerebral autoregulation, subjects were cooled via cooling blanket to 34.2±0.5°C for 40±45 hours. ICP significantly decreased from 23±4 to 18±5 mm Hg (P<0.05) after induction of hypothermia, however, autoregulation seemed to be minimally affected as the cerebral pressure reactivity index did not change (normothermia=0.00±0.21, hypothermia=-0.01±0.21). Patients were passively allowed to rewarm at an average rate of 0.2±0.2°C/h. On rewarming, there was no change in ICP (18±6 mm Hg at 37°C) or cerebral pressure reactivity index (0.06±0.18 at 37°C). However, in 17 patients, brain temperature exceeded 37°C (average brain temperature in this subset of patients=37.8±0.3°C) and this resulted in a significant increase in cerebral pressure reactivity index (0.32±0.24; P<0.0001 compared with hypothermia) despite no change in ICP (18±8 mm Hg, P=0.74 compared with hypothermia). This suggests diminished cerebral autoregulation. Even after correction for factors that may have influenced this observation (ie, brain pH and partial pressure of oxygen and carbon dioxide measured in pericontusional regions of white matter, cerebral perfusion pressure, and ICP), the impairment of autoregulation remained significant. Of note, 3 of 24 patients demonstrated impaired autoregulation (cerebral pressure reactivity index >0.2) before the induction of hypothermia and 13 of 17 had impaired autoregulation when brain temperature was >37.3°C.

Ischemic Preconditioning

In its simplest form, ischemic preconditioning refers to the exposure of an organ (eg, brain, heart) to a brief subclinical ischemic challenge such that cellular protective mechanisms can be induced before exposure to a more severe or second ischemic event. These protective mechanisms involve a variety of receptors (ie, [delta]-opioid, [gamma]-amino-butyric acid, N-methyl-D-aspartate, adenosine) and biochemical pathways. In 2007, Steiger and Hanggi 154 published a thorough review of the literature on ischemic preconditioning of the brain. The article reviews protective mechanisms and potential clinical applications of ischemic preconditioning.

Ischemic preconditioning generally consists of 2 phases of protective benefits: (1) the early phase, lasting up to 3 hours, seems to be the result of activation of various protein kinases and phosphatases and (2) the delayed phase, lasting up to 72 hours, is mostly dependent on changes in protein synthesis. The epsilon isoform of protein kinase C (nPKC[varepsilon]), activated during the early phase of ischemic preconditioning, is known to activate other protein kinases and extracellular signal-related kinases (ERKs). Both nPKC[varepsilon] and ERK isoform 1/2 (ERK1/2) (a protein important for hippocampal memory formation) are both increased in hippocampal slices after injury.155,156 Using a murine model of oxygen-glucose deprivation (OGD) in hippocampal slices, Jia et al 157 evaluated whether activation of nPKC[varepsilon] and ERK1/2 played a role in early phase ischemic preconditioning and whether this effect is mediated through N-methyl-D-aspartate receptor. Using 10 and 45 minutes of OGD as stimulus for ischemic preconditioning followed by severe ischemia, respectively, they discovered that (1) nPKC[varepsilon] is activated by both 10 and 45 minutes of OGD and N-methyl-D-aspartate treatment, (2) nPKC[varepsilon] activation is blocked by administration of an N-methyl-D-aspartate receptor antagonist, (3) neuronal cell death after 45 minutes of OGD (64%±1% cell death) is attenuated by preconditioning with either 10 minutes of OGD followed by normoxia (48%±2% cell death; P<0.05) or incubation with N-methyl-

D-aspartate (44%±2% cell death; P<0.05), (4) N-methyl-D-aspartate antagonist administration before and during ischemic preconditioning (10 min of OGD) resulted in increased cell death compared with ischemic preconditioning followed by severe ischemia alone, and (5) blocking of nPKC[varepsilon] and ERK activation attenuated ischemic preconditioning's neuroprotective benefits. In a related investigation involving rat hippocampal slices in a TBI/hypothermia model, Atkins et al 158 reported that ERK1/2-mediated pathways may be important mechanism accounting for hypothermia-induced neuroprotection.

There is much interest in developing a drug that could potentially activate these operant preconditioning pathways and provide neuroprotection without the need for subclinical ischemia. In a recent investigation, the macrolide antibiotic, erythromycin, induced a neuroprotective response similar to prior exposure to subclinical ischemia 159; however, the mechanism for this effect was poorly described. Using a rat model, Koerner et al 160 attempted to characterize changes in gene expression induced by the administration of erythromycin before cerebral ischemia. Rats were randomly assigned to receive 25-mg/kg intramuscular erythromycin or saline control 6 hours before either global ischemia (via carotid occlusion and hypotension to a mean arterial pressure of 35 mm Hg for 15 min) or sham operation. One hundred seventy-six of 1185 (15%) target genes were differentially expressed after ischemia compared with sham. Of those, 62% were up-regulated (predominantly involving genes responsible for RNA processing, DNA binding, transcription, and onco-suppressor and tumor-suppressor genes), and 38% were down-regulated (mostly involving those encoding for cytoskeletal proteins and DNA-binding proteins) (Fig. 7). In those with prior exposure to erythromycin, 130 of 1185 (11%) of genes were differentially expressed after ischemia compared with sham. A very different pattern of expression was observed as 31% of genes in erythromycin-treated rats showed up-regulation (mostly involving genes responsible for RNA processing, transcription, and cell surface antigens) and 69% were down-regulated (mostly involving genes encoding DNA-binding proteins, translation and cytoskeletal proteins) (Fig. 7). Erythromycin without ischemia resulted in a down-regulation of 9 genes, mostly those responsible for extracellular transporters and cytoskeletal proteins (Fig. 7). There was very little overlap of differentially expressed genes, suggesting that erythromycin has a significant affect on gene expression associated with brain ischemia. Overall, this study demonstrated that (1) erythromycin down-regulated gene expression after ischemia and (2) erythromycin, unlike classic preconditioning, does not induce protective genes but diminished the expression of genes, which may induce secondary damage. This research provides hope that drug-induced ischemia-like preconditioning may indeed become a reality.

FIGURE 7. Effect of erythromycin administration on gene expression after global cerebral ischemia in rats. A total of 1185 gene targets were grouped into 24 different categories. Up-regulated and down-regulated genes are indicated by gray and black bars, respectively. Administration of saline followed by 15 minutes of global ischemia (VEH+ischemia) showed a net up-regulation, mostly affecting genes involved in RNA processing, DNA binding,

transcription, and onco-suppressor and tumor-suppressor genes. Pretreatment with erythromycin before ischemia (ERY+ischemia) showed a net down-regulation of genes with those encoding for proteins responsible for DNA binding, translation, and cytoskeletal elements being mostly affected. Erythromycin without ischemia (ERY+30 h) resulted in a down-regulation of genes, mostly those responsible for extracellular transporters and cytoskeletal proteins. From Anesthesiology. 2007;106:538–547 with permission.

Anesthetic Agents and Cerebral Protection

The neuroprotective effects of the barbiturates have been widely studied.161 The mechanism of their protective effect has not been fully elucidated; however, it is probably owing to a combination of suppression of cerebral oxygen consumption, effects at a variety of ion channels, and minimization of glutamate release, and other mechanisms. Propofol, a newer and less-studied drug, has also been shown to have neuroprotective properties in an experimental setting.162 Using gerbils, Kobayashi et al 163 compared the duration of time needed to produce damage to 50% of hippocampal CA1 neurons upon ischemia during burst-suppressive doses of both sodium pentothal and propofol with control (1% end-expired halothane). During maintenance with either propofol or sodium pentothal (2.0 mg/kg/min until 5 min of burst suppression) or 1% end-expired halothane, cerebral ischemia of various durations (0, 3, 5, or 10 min) was induced in gerbils and the CA1 regions of the hippocampi were evaluated 5 days later for the degree of injury. Injured neurons were identified as having pyknotic nuclei with eosinophilic cytoplasm. After deriving probit curves via logistic regression, the ischemic time necessary to produce injury to 50% of neurons was 5.1, 6.5, and 8.4 minutes for halothane, propofol, and sodium pentothal, respectively (P<0.05 for propofol vs. halothane and for sodium pentothal vs. both propofol and halothane). To determine the effect of each agent on the characteristics of ischemic depolarization, DC currents were measured in the hippocampi of ischemic animals and the onset (time from initiation of ischemia until the sudden negative shift of DC potential) and duration (time from the sudden negative shift of the DC potential until 80% recovery from maximal deflection) were recorded. Propofol and sodium pentothal both prolonged the onset time of ischemic depolarization compared with halothane. After both 3 and 5 minutes of ischemia, both propofol and sodium pentothal decreased the duration of ischemic depolarization, however, after 10 minutes of ischemia, sodium pentothal, not propofol, significantly decreased the duration of ischemic depolarization. Reduction in the duration of ischemic depolarization is thought to lead to protective effects via 2 mechanisms: (1) attenuating increases in cerebral metabolism associated with neuronal depolarization and (2) attenuating glutamate accumulation, calcium influx, and the production of free radicals. To further characterize the differential effects of propofol and sodium pentothal, in a separate group of gerbils, glutamate concentrations were measured via microdialysis from the CA1 regions of hippocampi after 7.5 minutes of ischemia during burst-suppressive doses of either propofol or sodium pentothal, or 1% end-expired halothane. Maximum glutamate concentrations were significantly lower in both the sodium pentothal group (32.9±9.9 mM, P=0.001 vs. halothane) and propofol groups (52.5±8.4 mM, P=0.02 vs. halothane) compared with halothane (88.0±33.7 mM). There was no difference between the propofol and sodium pentothal groups (P=0.16). Collectively, these data suggest that sodium pentothal has superior protective effects against ischemic damage than propofol. Sodium pentothal had an observed tendency for greater reduction in the duration of ischemic depolarization at all durations of ischemia investigated versus propofol; however, this was only statistically significantly different at 10 minutes of ischemia. Also, there was a tendency toward lower glutamate concentrations in the extracellular fluid during ischemia with sodium pentothal compared with propofol. One must keep in mind that there were only 8 gerbils per group. It is possible that this investigation lacked power to detect the greater ability of sodium pentothal to shorten the duration of ischemic depolarization, thus reducing extracellular glutamate concentrations and attenuating glutamate excitotoxicity. Of further note, only high (ie, burst-suppressive) doses were evaluated and long-term effects (>5 d) after ischemia were not evaluated. Also, there were differences in the baseline characteristics (after anesthesia but before the induction of ischemia) among groups that may have confounded the findings; compared with animals in the halothane group, those in the propofol and sodium pentothal groups had: (1) a lower blood pH, (2) a higher PaCO2, and (3) lower mean arterial pressure. As such, further research is needed to test these results in other models.

Isoflurane has shown promising neuroprotective effects in the laboratory,164,165 however, some data suggest that this effect may be short-lived. Specifically, isoflurane seems to cause a reduction in the number of neurons

undergoing necrosis (in the short term), but may increase the number of neurons that eventually perish via an apoptotic mechanism of cell death.166–168 Some question whether other variables within the experimental models may partially account for this finding. Using a rat model of focal ischemia, Sakai et al 169 evaluated the impact of experimental factors on both functional and histologic outcome in isoflurane-anesthetized animals. In a series of experiments, they were able to demonstrate improved neurologic outcome and reduced infarct volume at both 2 and 8 weeks after temporary focal ischemia in rats anesthetized with 1.8% end-expired isoflurane compared with those that had ischemia while awake. Furthermore, infarct volume in both awake and anesthetized rats was independent of ischemic time (50 min vs. 80 min) at 2 weeks postischemia. Also, augmentation of blood pressure during isoflurane anesthesia with phenylephrine (mean arterial blood pressure during ischemia was approximately 110 to 120 mm Hg vs. 80 to 90 mm Hg) or administration of a mitochondrial potassium adenosine triphosphate channel antagonist did not influence infarct volume or functional outcome, suggesting that isoflurane may provide sustained neuroprotection against injury from focal ischemia independent of these manipulated variables.

It has only been recently demonstrated that neuronal regeneration via progenitor cells can occur within the brain 170; however, a stimulus, such as ischemia, is probably needed to initiate the process. Engelhard et al,171 used a rat model to determine whether neuronal regeneration is augmented by volatile anesthetics. Forty rats were divided into 5 equal groups: (1) 1.4% end-expired sevoflurane with no ischemia, (2) 1.4% end-expired sevoflurane with ischemia, (3) 2.8% end-expired sevoflurane with no ischemia, (4) 2.8% end-expired sevoflurane with ischemia, or (5) no sevoflurane and no ischemia. Cerebral ischemia was induced via bilateral carotid occlusion with hemorrhagic hypotension to a mean arterial blood pressure of 40 mm Hg for 10 minutes. Rats received BrdU, a marker of DNA synthesis, for 7 days and were killed at 28 days. Dentate gyrus sections were then stained with NeuN (which labels differentiated neurons) such that cells staining positive for both BrdU and NeuN represent newly generated, differentiated neurons. Although there was a tendency toward increased neurogenesis in animals that had 1.4% end-expired sevoflurane and ischemia, the amount of BrdU+ and NeuN+ cells was not different from controls (1.4% sevoflurane and no ischemia or those that received neither sevoflurane or ischemia). However, rats that had cerebral ischemia during 2.8% end-expired sevoflurane not only had more evidence of injury (ie, cytoplasmic eosinophilia and pyknotic nuclei) but also had a statistically significant 230% increase in newly generated neurons compared with those that received the same concentration of sevoflurane but did not have ischemia. Although the authors concluded that both high-dose sevoflurane and ischemia are needed to foster sustained neurogenesis, they failed to comment on the presence of BrdU and NeuN-positive cells in animals that received neither sevoflurane nor ischemia. Although it was clearly beyond the scope of this investigation, a causal correlation between increased neurogenesis and improved functional outcome is yet to be established. Nevertheless, this preliminary research does offer some promising findings.

SPINE SURGERYAirway Management in Patients With Cervical Spine Disease

In patients having acute and chronic cervical spine disease, great care is taken during airway management to avoid inducing new injury or exacerbating existing injury to the cervical spinal cord. In patients with acute injury, manual in-line stabilization of the neck can minimize mobility of anatomic structures, thus reducing the risk of cervical cord injury.172 However, the reduced mobility from in-line stabilization also may make direct visualization of glottic structure difficult. A variety of alternative techniques exist for airway instrumentation; however, the safety of these alternate techniques has been documented for only a few. The Airtraq laryngoscope (Prodol Ltd, Vizcaya, Spain) is similar to the Bullard laryngoscope in that both are anatomically shaped, rigid fiberoptic laryngoscopes that allow tracheal intubation with minimal neck movement. However, unlike the Bullard laryngoscope, the single-use, disposable Airtraq scope contains a channel (in contrast to the Bullard's stylette) to guide the tube into the trachea. In one prospective, randomized investigation, Maharaj et al 173 compared the utility of the Airtraq laryngoscope with direct laryngoscopy with a Macintosh blade, both during manual in-line stabilization in 40 patients undergoing surgery requiring endotracheal intubation. Patients were excluded if they had factors suggesting that tracheal intubation might be difficult (ie, Mallampati class III or IV, thyromental distance <6 cm, interincisor distance <4 cm). The authors do not state whether patients with cervical spinal cord concerns were included in this investigation. Airtraq use, when compared with the Macintosh blade, significantly reduced the time required for intubation (13.2±5.5 s vs. 20.3±12.2s; P<0.05), reduced the percentage of patients

requiring optimization maneuvers (0% vs. 40%; P<0.05), and minimized increases in both heart rate and mean arterial blood pressure.

Using a rigid fiberoptic scope similar to the Airtraq, Hirabayashi et al 174 radiographically compared cervical spine motion during tracheal intubation in 20 patients without anticipated airway difficulty, randomized with either the Airway Scope (Pentax, Tokyo, Japan) or direct laryngoscopy with a Macintosh blade. The authors demonstrated that although both techniques resulted in extension at all vertebral levels investigated (ie, occiput-C1, C1 to C2, C2 to C3, and C3 to C4), significantly less extension was observed at all levels except C2 to C3 with the Airway Scope. In addition to comparing these devices only in patients with expected “easy airways,” this latter investigation did not introduce in-line stabilization during airway instrumentation. As such, additional research is needed to address the clinical scenario in which laryngoscopy is attempted during in-line stabilization of the cervical spine.

In actual clinical practice, the approach to airway management in the patient experiencing, or at risk for, cervical spine injury will be influenced by a variety of anatomic and systemic physiologic factors. In an observational prospective cohort study, Manninen et al 175 documented the approach to airway management in 327 patients presenting for cervical spine surgery. The tracheas of 39% of patients were intubated fiberoptically before induction of general anesthesia and 61% were intubated after induction. Of those intubated “asleep,” 52% were intubated fiberoptically, 36% via direct laryngoscopy, and 12% via other techniques such as the GlideScope (GUL, Saturn Biomedical Systems, Burnaby, Canada) or Trachlight (Laerdal Medical Corporation, Wappingers Falls, NY). Awake fiberoptic intubation was predominantly chosen for patients with: (1) myelopathy, (2) unstable or fractured spinal elements, (3) stenosis of the central canal, (4) posterior (vs. anterior) surgical approach to the cervical spine, (5) potentially difficult airways, and (6) need for emergency surgery. Those with radicular symptoms were typically intubated fiberoptically after induction of anesthesia and those with spinal tumors were typically intubated via direct laryngoscopy. There were no associations between postoperative airway complications and the method chosen for intubation. The authors attributed the higher incidence of fiberoptic intubation used with cases involving a posterior (vs. anterior) approach to the cord to: (1) the high incidence of those with unstable elements or myelopathy or (2) those needing spinal decompression and fusion. Given the lack of association between choice of airway technique and postoperative complications, the authors recommend that anesthesiologists make their choices on a case-by-case basis and use patient characteristics and knowledge of their individual skills to make an informed decision.

Ocular Disorders After Spine Surgery

In recent years, much attention has focused on visual changes or loss after spine surgery, especially in those cases of visual loss attributed to posterior ischemic optic neuropathy. Central retinal artery occlusion, another potential cause of perioperative visual loss associated with spine surgery, is less common than posterior ischemic optic neuropathy; however, it can be equally devastating. Given the rarity of central retinal artery occlusion, it is difficult to determine risk factors; however, an association with periocular trauma has been suggested.176 We identified 2 case reports published in 2007 that support this concept. In one case, central retinal artery occlusion occurred in a 12-year-old girl after repeat high cervical spine surgery.177 The patient was positioned prone with her head on a horseshoe headrest. Although care was taken to avoid pressure on the eyes during initial positioning, the report makes no mention that proper intraoperative positioning was periodically confirmed (although that may have proven difficult given the nature of the surgery). The patient experienced confirmed central retinal artery occlusion, and permanent unilateral blindness resulted despite attempted treatment with mannitol and acetazolamide.178 The attribution of this adverse outcome to external pressure on the globe by the horseshoe headrest reinforces the importance of frequent position checks to confirm safe eye positioning during surgery. In a separate report, Roth et al 179 describe the development of central retinal artery occlusion in a 53-year-old male patient who underwent a single-level lumbar fusion. The patient's eyes were covered with Dupaco Opti-Gard Eye Protectors (Dupaco, Oceanside, CA) and his head was positioned on a Gentle-touch foam headrest (Orthopedic Systems, Union City, CA). At the conclusion of surgery, the patient had a new abrasion of the upper eyelid and suffered from ipsilateral permanent visual loss owing to central retinal artery occlusion. This was attributed to trauma sustained from the eye Opti-Gard Eye Protector. The report states that the anesthesia provider blindly palpated the edge of the

protector during surgery, but did not appreciate that the plastic lens of the device was exerting pressure on the globe.

Although usually not as devastating as central retinal artery occlusion or ischemic optic neuropathy, ocular chemosis (ie, conjunctival edema) can—in patients having surgery in the prone position—be a cause of short-term decreased visual acuity, patient discomfort, and increased risk for bacterial keratitis.180 Jeon et al 181 prospectively determined risk factors for chemosis after prone spine surgery. One hundred and eight patients were randomized to have their head positioned neutral (ie, an imaginary line drawn between the C7 spinous process and the occipital protuberance was horizontal to the floor) or 5-cm head down. The incidence of chemosis was significantly greater in the head-down patients (46% vs. 30%; P<0.05). They found that significant risk factors for chemosis were (1) head-down position [OR=8.8 (CI=2.3-33.5); P=0.001 vs. neutral position], (2) positive fluid balance >700 [OR=6.3, (CI=1.6-24.1); P=0.007 for <700 mL vs. 700 mL to 1399 mL and OR=32.8 (CI=2.7-403); P=0.006 for <700 mL vs. >1400 mL], and (3) surgical duration >=180 minutes [OR=14.0 (CI=2.4-80); P=0.003 for <120 min vs. >=180 min]. Estimated blood loss was not associated with increased risk (P=0.879, OR not reported). Of note, the authors did not comment on the relationship of the head to the thorax or heart (ie, factors that could possibly be just as important as neck position) or on other complications possibly related to neck position (eg, pressure ulcers on the face, neck pain, or injury to the cervical spine).

Anesthesia Maintenance Techniques During Spine Surgery

Inhalational anesthetics are commonly used for maintenance of general anesthesia during spine surgery, but little is known about their effect on incidence of PONV in this senario.182 In a prospective nonrandomized cohort investigation involving 625 patients presenting for lumbar spine surgery, Wallenborn et al 183 compared anesthesia maintenance with either sevoflurane, isoflurane, or desflurane on PONV, and also evaluated for other, anesthetic-independent risk factors. The anesthetic groups were nonconcurrent; patients having surgery: (1) in 2002 received isoflurane (0.7% to 1.2% end-expired, N=215), (2) in 2003 received desflurane (3.5% to 5.5% end-expired, N=206), and (3) in 2004 received sevoflurane (1.2% to 1.9% end-expired, N=204). All patients underwent a standardized induction of anesthesia with either sodium pentothal or etomidate and received standardized doses of the antiemetics metoclopramide and dexamethasone before emergence; nitrous oxide was not used in any case. There were significant differences among groups with respect to various demographics: (1) percentage of patients positioned in a genupectoral position (vs. a Wilson frame) (41%, 54%, and 98% for isoflurane, desflurane, and sevoflurane, respectively, P<0.001) and (2) those receiving high-dose dexamethasone (41%, 36%, and 24% for isoflurane, desflurane, and sevoflurane, respectively, P<0.001), and those receiving postoperative opioids (45%, 61%, and 62% for isoflurane, desflurane, and sevoflurane, respectively, P<0.001). They found no difference among groups in the incidence of PONV within 24 hours of surgery (9.3% for isoflurane, 11.2% for sevoflurane, and 10.8% for desflurane, P=0.803) or the need for rescue antiemetics (4.2% for isoflurane, 3.9% for sevoflurane, and 2.5% for desflurane, P=0.592). They did find that episodes of PONV were more likely to occur early (<6-h postoperative) with sevoflurane and desflurane, but occurred both early and late (<12-h postoperatively) with isoflurane. They confirmed known risk factors for PONV (ie, female sex, nonsmoking status, and history of PONV or motion sickness), and also reported that after correcting for surgical duration, patients in the genupectoral position had a higher risk of PONV than those in whom the Wilson frame was used [OR=1.98 (CI=1.06-3.70, P=0.032)]. A longer duration of general anesthesia, not surgical stimulation, associated with a greater risk of PONV [OR/10-min unstimulated time=1.36 (CI not reported), P<0.001]. The authors attributed the association with duration of general anesthesia without surgical stimulation to probable deeper hypnotic concentrations of volatile anesthetics, but they did not provide a possible explanation for the relationship between positioning and PONV.

Pneumocephalus after both craniotomy and dural puncture during regional anesthesia have both been well-described.184–186 Currently, the incidence of pneumocephalus after spine surgery requiring durotomy is unknown. Turgut et al 187 determined the incidence of pneumocephalus in patients undergoing thoracic or lumbar spinal intradural tumor resection and hypothesized that the application of 5 cm H2O of positive end-expiratory pressure (PEEP) during mechanical ventilation would reduce the incidence of postoperative pneumocephalus. Anesthesia was maintained via a propofol infusion with supplemental narcotics and patients were ventilated with a

1:1 air:oxygen mixture and were randomized to receive either 0 or 5 cm H2O of PEEP during mechanical ventilation. Those ventilated with 5 cm H2O of PEEP had a reduced incidence of pneumocephalus (4%) compared with those ventilated without PEEP (28.6%) (P=0.026). The quantity of intracranial air, determined via cranial computerized tomography using BAB Bs200Pro P Image System software (BAB Industries, Ankara, Turkey), was 0.03 to 4.24 cm2. Two patients in the non-PEEP group developed symptoms of headache and altered level of consciousness, which was attributed to the presence of pneumocephalus as other possible causes were ruled out. Data from this study suggest that pneumocephalus is actually quite common after spine surgery requiring durotomy. One limitation of this investigation was that air was quantified in a cross-sectional area instead of a 3-dimensional volume.

CONCLUSIONS

The 2007 literature contains a wealth of articles that are relevant to practitioners and investigators interested in the care of neurosurgical and neurologically impaired patients. This overview is intended as an introduction to the highlights of that literature. Readers interested in the topics addressed in this overview are encouraged to review the referenced articles for further details.

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Key Words: subarachnoid hemorrhage; traumatic brain injury; neuroprotection; spine surgery; carotid endarterectomy